PROJECT SUMMARY Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder caused by interactions among multiple genetic and environmental factors. A large body of evidence has convincingly demonstrated that sex is a major source of disease heterogeneity and physiologic status. Sex differences in the risk of AD, vulnerability to apolipoprotein (apo) E genetic load, and severity of AD pathology burden have been established. In addition to these direct contributors to disease, sex-differences also exist for many of the physiological and co-morbid conditions known to be risk factors for AD, most notably age-related inflammation. Although the sex differences in the risk of AD, vulnerability to genetic load and severity of AD pathology burden have been well established, the molecular underpinnings and pathways that are differentially mediated in male and female AD patients are still poorly understood. The difference in immunity and inflammatory response during AD process is another source of the disease heterogeneity; however, the underlying mechanisms remain elusive. Precision medicine is an emerging integrative approach for disease prevention, early detection, and treatment, which takes into account individual variability in genetics, epigenetics, sex, environment, and lifestyle. The current and ever-growing availability of public `omics data of normal and AD brains, including Gene Expression Omnibus, Array Express and the new National Institute of Aging's Accelerating Medicines Partnership for Alzheimer's Disease portal (AMP-AD), along with emerging single cell sequencing technologies and computational tools to dissect molecular drivers of disease at a network level, present a unique new opportunity to query the interactive effects of apoE4 with sex and inflammation on AD pathogenesis at the genomic, transcriptomic and single cell level. By capitalizing on this promise, this proposal aims (1) to analyze publicly available, large-scale transcriptomic datasets of AD patients and age-matched controls to identify sex and apoE genotype-specific gene expression signatures of AD, (2) to analyze publicly available, large-scale genomic datasets of AD patients and age-matched controls to identify genomic regions that are associated with AD differentially in male and female patients and examine their interactive effects with apoE genotypes, and (3) to leverage single nucleus RNA-Seq technology to examine sex and apoE genotype specific transcriptomic signatures in an established mouse model of AD and evaluate their relevance to human data. We aim to specifically interrogate inflammatory and immune pathways both on the genomic and transcriptomic level in mice and humans throughout our three specific aims to elucidate the mechanisms by which these pathways lead to the disease and genotype specific differences in men and women with AD.The outcomes of the proposed studies will shed light on the molecular pathways that might explain the sex differences in the pathogenesis of AD and which in turn can inform precision medicine diagnostic and therapeutic strategies.